Medications for the treatment of respiratory disorders are commonly administered by inhalation through the mouth or nose in an aerosol formulation. As with any other delivery method, safety, toxicity and bioavailability, are the main concerns. The inhalation route can provide superior advantages for the treatment of pulmonary diseases, as compared with other means of administration such as oral or injection. Injection is the most effective method of administration to a patient's blood stream, however it is a painful administration procedure, and systemic side effects may occur from the unwarranted spread of drug molecules such as steroids and beta-blockers. While oral intake is the preferred alternative for drug administration, it often requires large doses of the medication in order to be effective, which can result in unwanted side effects. Drug delivery by inhalation can effectively deposit a medication locally at a targeted therapeutic site, thereby providing rapid onset, a lower dosing requirement and decreased incidence of side effects.
One of the most widely used devices to deliver a formulation through the inhalation method for the treatment of pulmonary disorders is a metered dose inhaler (MDI). The MDI is widely used for the delivery of bronchodilator type products for the treatment of respiratory disorders such as Chronic Obstructive Pulmonary Disease (COPD) and asthma. The MDI has gained popularity since its introduction decades ago, mainly because administration is convenient and practical. Additionally, the MDI is easy to use, portable, capable of multiple dose delivery, low cost, provides minimal loss of drug within the device at the time of administration, and is a reliable and efficient method of drug delivery to a targeted area of the patient's lungs.
Prior art metered dose inhaler formulations have historically contained chlorofluorocarbon (CFC) as propellants to deliver doses of medication to a patient's lungs. However, CFCs have been associated with the degradation of the ozone layer. Depletion of the ozone layer causes an increase of UV light exposure, which is responsible for numerous health problems such as increased incidence of skin cancer, premature aging of the skin, cataracts/eye damage and suppression of the immune system. The use of CFC's is being phased out as part of the agreement of the Montreal protocol Exceptions have been made for certain uses that are necessary for health and safety, which include MDIs for pharmaceutical use These types of products will be gradually phased out as substitutes become available.
The phasing out of CFCs has led to a flurry of development activities for alternative means of pulmonary drug delivery without the use of CFC propellants. One previous alternative is the use of nebulizers. A nebulizer is pressurized by an oxygen tank or oil free compressed air source for the purpose of vaporizing a liquid medication into a fine mist that is suitable for delivery via the respiratory tract without the use of CFCs. However, nebulizers are expensive and inconvenient for patients because there are problems with dosing uniformity, and nebulizers require a power supply for operation, are cumbersome and require a longer time for drug delivery. A nebulizer is mainly used in an emergency room or for children and elderly patients who cannot operate an MDI themselves.
Another alternative to CFCs that is gaining popularity is a dry powder inhaler (DPI). A DPI has several advantages as it contains no propellant and is breath activated, thus eliminating the need to synchronize inhalation with actuation. However, DPIs do present formulation challenges for delivering micrograms of drug molecules uniformly from dose to dose. A micronized drug has to be mixed with a coarse carrier substance such as lactose, which can cause airway irritation in some asthmatic patients.
Over the years improvements have been made to the drug delivery systems, such as multidose DPIs and more versatile nebulizers that increase convenience and ease of use to patients. However, the advantages and superiority of a MDI remain unchallenged, which is the reason that MDIs remain as the most popular and widely used inhalation delivery device. Thus, reformulation of CFC based medicinal aerosols using a MDI appears to be the best solution. The phase out of CFCs has made this an urgent matter, which has also turned out to be an opportunity to improve the performance of MDIs.
Hydrofluoroalkane (HFA) propellants have emerged as the best alternative to replace CFC propellants in a MDI for pharmaceutical uses. HFA-134a with chemical formula 1,1,1,2-tetrafluoroethane, and HFA-227 with chemical formula 1,1,1,2,3,3,3-heptafluoropropane are considered the most suitable alternative propellants. The development of a new formulation utilizing HFA has proven to be a difficult challenge because this propellant tends not to function with CFC compatible excipients due to differences in the chemical and physical properties of these two propellants. Thus, there is a necessity to develop a new formulation that provides an effective MDI formulation utilizing HFA propellant.
Epinephrine is commonly used as a bronchodilator in the treatment of acute bronchial asthma. Currently, inhalable Epinephrine is only available in CFC form under the name Primatene® manufactured by Armstrong Pharmaceuticals, Inc. Primatene® is a CFC/alcohol solution of epinephrine. It is supplied with a glass bottle because of its low pH due to hydrochloric acid and nitric acid in the CFC formulation. Historically, CFC based MDI formulations with Epinephrine have a problem of low respirable fractions or drug delivery efficiency, and high throat deposition requiring large drug doses to obtain therapeutic efficacy. In addition, epinephrine formulation is easily oxidized which can cause the formulation to become unstable. According to Analytical Profiles of Drug Substances, Vol. 7, p. 213, “Since epinephrine is an o-diphenol containing a hydroxyl group in the α position, it is a strong reducing agent. As such, it is easily oxidized by such oxidizing agents as molecular oxygen. Oxidation of epinephrine by molecular oxygen can also result in formulation of a brownish insoluble material of indefinite structure.”
Applicants have now discovered a new epinephrine suspension formulation with improved formulation characteristics that solves prior art problems by eliminating the use of CFCs and adding an antioxidant to produce a stable formulation that exhibits a significantly higher drug deposition in the respirable region of a patient's lungs.
A search of the prior art reveals numerous patents for the preparation of MDI formulations that contain no CFC propellant or contain HFA propellant. However, none of the prior art patents possess the novelty of the instant invention, which introduces a high efficiency stable MDI suspension formulation containing epinephrine or its salt forms with HFA as the propellant for the treatment of asthma, COPD and other respiratory disorders.